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To search for host genes for resistance/susceptibility to cancer metastasis, mutation analysis was employed. Ten putative mutants of resistance to lymphoma EL4 and four putative mutants of resistance to sarcoma MCA/77-23 of C57BL/6J (B6) mice were produced. These mutants were designated S (for "survivor") mutants; they do not reject parental strain B6 skin grafts. S-mutants resist moderate tumor cell doses: TD50 values in them were increased by a factor of 12 to 600. Genetic linkage tests showed that five S-mutants were linked to mouse major histocompatibility complex (H-2) and five other S-mutants were not linked to this locus. A group of H-2-linked S-mutants resisting EL4 and a mutant, S-87/2, resisting MCA/77-23 were tested for resistance to spontaneous metastases of the same two tumors, EL4 and MCA/77-23. Two of the mutants, S-31 (lymphoma-resisting) and S-87/2 (sarcoma-resisting), were shown to carry mutations of mouse gene(s) for resistance to tumor metastases. In both of these mutants resistance to the original tumor transplant coexisted with highly increased susceptibility to metastasis. These mutants are a new tool to study genes for resistance to cancer metastasis and of mechanism of resistance controlled by each individual gene.

"S" (survivor) mutants were produced in mice for genetic analysis of host resistance to metastatic cancers. S-mutants S-27 and S-31 resist transplantation of lymphoma EL4 of parental C57BL/6J (B6) mice while they accept parental skin grafts. Mutant S-27 also resists formation of spontaneous metastases from intradermally growing EL4 tumor into lymph nodes; mutant S-31 is highly susceptible to EL4 metastases. Another mutant, H-2bm26 (bm26), resists EL4 and rejects B6 skin grafts. Major histocompatibility complex (MHC) class I and class II gene expression was compared in these mutants and normal B6 mice. All three mutants tested, S-27, S-31, and bm26, expressed a low amount of Kb mRNA in organ-specific fashion. Mutants bm26 and S-31 expressed a low amount of Abb mRNA and of Ab antigen on their spleen cells. Some oligonucleotide probes designed to hybridize to the second exon of the class II MHC gene Abb did not hybridize with DNA from all three mutants. These findings suggest extensive sequence alterations in the Abb gene in mutants S-27, S-31, and bm26; they also suggest a major role of MHC in the control of host resistance to spontaneous metastases of the EL4 tumor.

Gene conversion is often invoked to explain the evolution of sequence patterns observed in major histocompatibility complex (MHC) genes and their alleles. This is the gene conversion hypothesis of MHC sequence evolution. These observations and their interpretation probably belong in a larger theoretical framework, namely the evolution of systems of resistance to rapidly evolving pathogens. This review looks critically at the evidence in favor of the gene conversion hypothesis in this context. We conclude that the case for the existence of an adaptive mechanism in the MHC favoring gene conversion mutations is not proven. [ABSTRACT FROM AUTHOR]

We examined 32 DNA sequences of mouse and human major histocompatibility complex (MHC) genes believed to have been subjected to gene conversion events. All regions of the mouse H2 genes as well as the human HLA genes which have been implied to be involved in gene conversion events had elevated levels of CpG dinucleotides, whereas the rest of the genes showed extensive CpG suppression. Mouse MHC genes which have been suspected but not directly implied to be involved in gene conversion events also showed elevated levels of CpG dinucleotides. Moreover, both mouse and human MHC genes which have never been suspected of undergoing gene conversion had low levels of CpG throughout the genes. These results indicate that high CpG levels are correlated with gene conversion rather than with polymorphism, as non-polymorphic genes that have been implicated as gene conversion donors also have elevated levels of CpG dimers in the involved regions, whereas polymorphic genes which have never been considered to undergo gene conversion events have a low level of CpG dinucleotides. We also studied the methylation pattern of CpG dimers in the Abk gene by restriction enzyme digestion of mouse testis DNA followed by Southern blot and hybridization to an Abk-specific probe. The examined CpG dimers in prepubescent mice, where the latest germline stages are spermatogonia, leptene, or pachytene, are respectively non-methylated. Accordingly, the CpG dimers appear to be non-methylated in germline DNA from the testis of prepubescent mice, where gene conversions have been reported to occur. [ABSTRACT FROM AUTHOR]